Structure-activity Relationship Study of Permethyl Ningalin B Analogues as P-glycoprotein Chemosensitizer.

Journal of medicinal chemistry

PubMedID: 24171478

Bin JW, Wong IL, Hu X, Yu ZX, Xing LF, Jiang T, Chow LM, Biao WS. Structure-activity Relationship Study of Permethyl Ningalin B Analogues as P-glycoprotein Chemosensitizer. J Med Chem. 2013;.
A novel series of permethyl ningalin B analogues were synthesized and evaluated for their P-gp modulating activities in P-gp-overexpressing breast cancer cell line (LCC6MDR). Compounds 35 and 37, which possess one methoxy group and one benzoloxy group at aryl ring C, displayed the most potent P-gp modulating activity. 1 ┬ÁM of 35 and 37 re-sensitized LCC6MDR cells towards paclitaxel by 42.7-fold, with respective EC50 of 93.5 and 110.0 nM. Their mechanism of P-gp modulation is associated with an increase in intracellular drug accumulation. Their advantages also include low cytotoxicity (IC50 for L929 fibroblast > 100 ?M) and high therapeutic indexes (> 909 after normalizing with their EC50 values). 35 is not a substrate of P-gp. They are potentially dual selective modulators for both P-gp and BCRP transporters. The present study demonstrates that these new compounds can be employed as effective and safe modulators of P-gp-mediated drug resistance in cancer cells.